Male circumcision and risk of HIV infection in sub-Saharan Africa: a
systematic review and meta-analysis.

21/7/00

Helen A Weiss

Maria A Quigley

Richard J Hayes

Medical Research Council Tropical Epidemiology Group

London School of Hygiene & Tropical Medicine

Corresponding author (and address for reprint requests):

Helen A Weiss

Infectious Disease Epidemiology Unit

Department of Infectious and Tropical Diseases

London School of Hygiene & Tropical Medicine

Keppel Street

London

WC1E 7HT

UK

Running title: Meta-analysis of circumcision and HIV

3874 words excluding references and summary

Summary

Objective: To systematically review studies of male circumcision and risk
of HIV-1 infection in men in sub-Saharan Africa, and to summarize the findings
in a meta-analysis.

Design: Meta-analysis of observational studies

Methods: A systematic literature review of studies published up to April
1999 that included circumcision as a risk factor for HIV-1 infection among males
in sub-Saharan Africa was carried out. A random-effects meta-analysis was used
to calculate a pooled relative risk (RR) and 95% confidence interval (CI) for
all studies combined, and stratified by type of study population. Further
analyses were conducted among those studies which adjusted for potential
confounding factors.

Results: 27 studies were included. Of these, 21 showed a reduced risk of
HIV among circumcised men. HIV risk among circumcised men was around half that
in uncircumcised men (crude RR=0.52, CI 0.40-0.68). In the 15 studies that
adjusted for potential confounding factors, the association was even stronger
(adjusted RR=0.42, CI 0.34-0.54). The association was stronger among men at high
risk of HIV (crude RR 0.27; adjusted RR=0.29, CI 0.20-0.41) than among men in
general populations (crude RR 0.93; adjusted RR=0.56, CI 0.44-0.70).

Conclusions: Male circumcision is associated with a significantly reduced
risk of HIV infection among men in sub-Saharan Africa, particularly among men at
high risk of HIV. These results suggest that consideration should be given to
the acceptability and feasibility of providing safe services for male
circumcision as an additional HIV prevention strategy in areas of Africa where
men do not traditionally circumcise.

HIV prevalence in the general population in Africa varies widely both within
and between countries. The magnitude of the variation seems to be only partly
explained by different sexual behaviour patterns or factors known to influence
HIV transmission, such as presence of sexually transmitted diseases (STDs) or
condom use [1]. The hypothesis that male circumcision may reduce the risk of
acquiring HIV infection was first suggested early in the HIV epidemic [2], and
many epidemiological studies have since included circumcision as a potential
risk factor in studies of HIV infection.

There is substantial evidence that circumcision is associated with a reduced
risk of ulcerative STDs such as chancroid and syphilis [3]. As STDs, both
ulcerative and non-ulcerative, are known to enhance risk of acquiring and
transmitting HIV [4], it is likely that circumcision has an indirect effect on
HIV infection. Circumcision may also protect against HIV directly, as viral
entry may occur through micro-traumatic lesions or mini-ulcerations of the
foreskin [5] or through trauma to the non-keratinized inner mucosal surface of
the foreskin [6]. Further, the foreskin contains a higher density of Langerhans
cells than the urethra or rectum [7], and these cells may be primary target
cells for HIV transmission [8]. Genital ulcers may also be less easily
recognised in uncircumcised men, thus delaying treatment and increasing
susceptibility to HIV [6].

Male circumcision is practiced in many parts of Africa, but there is wide
regional variation [5, 9]. In particular, there are many ethnic groups in
eastern and southern Africa in which male circumcision is not traditionally
practiced. This area of non-circumcision covers most of Uganda, parts of western
Kenya, western Tanzania, north-eastern Democratic Republic of the Congo,
virtually all of Rwanda, Burundi, Zambia, Malawi and Zimbabwe, and parts of
Botswana, Namibia, Mozambique and South Africa. Circumcision is almost
universally practised in most parts of West Africa, including Nigeria. There is,
however, a large area of traditional non-circumcision covering central/eastern
Ivory Coast and western/central Ghana.

Within Africa, there is a broad correlation between areas where there is
little circumcision, and those with high HIV rates [5, 9]. This ecological
association means little however, without looking at individuals within
populations, and taking into account other factors associated with circumcision
status. There may be other factors associated with HIV risk (such as sexual
mixing patterns, or presence of other STDs) which are less prevalent among
circumcising than non-circumcising populations.

There have been four previous reviews of the literature on HIV and male
circumcision [3, 10-12]. The present review differs in being restricted to
female-male transmission in sub-Saharan Africa, where heterosexual transmission
is the predominant mode of transmission. It thus addresses the specific role of
male circumcision in the heterosexual acquisition of HIV in Africa. Only one
previous meta-analysis of the role of circumcision in HIV transmission has been
performed [12], and this had several statistical and epidemiological limitations
[13]. A re-analysis of the studies included in that report found that
uncircumcised men were at a significantly increased risk of HIV infection, but
concluded that a systematic review of the literature was urgently needed to
minimize bias, and to clarify the issue [14].

Materials and Methods

The aim of our literature search was to identify all published studies of
risk factors for HIV-1 infection among men in sub-Saharan Africa that included
circumcision as a potential risk factor. The Medline, Pre-Medline, HealthStar
and Popline databases were searched for papers published up to April 1999 which
included ‘circumcision’ and ‘HIV’ as keywords or text in the abstract. 22
original research papers were identified in this way, 20 of which appeared in
Medline. A further Medline search was carried out using keywords to search for
all published studies of HIV risk factors in men in sub-Saharan Africa using the
search condition (‘HIV-infections (epidemiology, etiology, transmission)’ OR
‘HIV-seroprevalence’ OR ‘HIV-seropositivity (epidemiology, transmission)’) AND
‘sub-Saharan Africa’ AND (‘risk factors’ or ‘odds ratios’ or ‘risk’)). 397
articles were identified in this way, including all 20 papers identified in the
initial search. Of these, the abstracts of 59 papers referred to risk factors
for female-male transmission of HIV, and these papers were manually scanned for
references to circumcision, yielding a further 7 eligible papers. Finally, the
reference lists of all 29 papers were checked, and 9 further potential papers
were identified. However, none of these included circumcision as a risk factor.
We did not include papers that used a proxy for circumcision, such as Muslim
religion. Conference abstracts were also excluded.

Of the 29 eligible papers, two were studies of risk factors for HIV-2 only,
and were excluded from the analysis [15, 16]. A further three studies contained
insufficient details to calculate a crude relative risk and were excluded from
the meta-analysis [17-19]. These studies were relatively small (study sizes of
125, 81 and 63 men respectively) and thus unlikely to have influenced the
meta-analysis substantially. One study [20] did not report a crude relative
risk, but did report an adjusted relative risk, and was included in the adjusted
meta-analysis.

Several studies from Mwanza, Tanzania appeared in more than one publication.
To avoid duplication of data in the meta-analysis, study 1 and study 5 from the
Urassa paper [21] were excluded because they were included elsewhere [22, 23]. A
study by Barongo et al. [24] was a subset of Urassa study 4, and was
excluded. Another eligible paper [25] was not included as the study population
formed the basis for a case-control study which allowed adjustment for
confounding variables [22].

Three papers included stratified analyses of different population groups, and
these strata were included as separate studies in the meta-analysis to reduce
confounding [23, 26, 27].

It is plausible that the effect of circumcision varies according to
background prevalence of HIV and of co-factors such as ulcerative STDs. Three
broad groups of studies were identified - population-based studies [21-23, 26,
28-31]; studies of men at high risk of HIV [20, 27, 32-41]; and other studies
(of factory workers and volunteers) [21, 42, 43]. Sub-group analyses were
carried out on the population-based and high-risk studies.

All types of study design (cohort, case-control and cross-sectional studies)
were included in the main analysis, and analyses were also carried out for
cross-sectional studies alone. In case-control and cross-sectional studies, the
odds ratio was used as an estimate of the risk ratio. The odds ratio was used in
cross-sectional studies because it is not possible to obtain an adjusted risk
ratio from published data as these were calculated using logistic regression.

However, when prevalence of HIV in the population is greater than about
20-25%, the odds ratio will be more extreme than the risk ratio. The sensitivity
of the meta-analysis to the measure of effect was assessed by re-analysing the
data for cross-sectional studies using the risk ratio. Statistical and graphical
analyses were performed using Stata 6 [44]. A random effects meta-analysis was
used to calculate a pooled relative risk (RR) [45, 46]. This model assumes a
different underlying effect for each study, and heterogeneity between studies
was also assessed [46]. Publication bias was assessed with a funnel plot and
Begg’s Test for correlation between the effect estimates and their variances
[47, 48].

Results

The studies included in the review are shown in Table 1, grouped by type of
population. The review incorporated 28 studies (19 cross-sectional, five
case-control, three cohort and one partner study) reported in 22 published
papers. The studies covered a range of population types, including general
populations (11 studies), STD clinic attenders (8 studies), truck drivers (3
studies), factory workers (2 studies), and TB patients, hospital patients,
volunteers and married couples (one study of each).

Meta-analysis

Crude relative risks were reported in 27 studies (see Table 1; Figure 1a).
One study [20] reported an adjusted RR but not a crude RR. In 21 of the studies,
circumcised men were at lower risk of HIV than uncircumcised men, and the
association was statistically significant (p<0.05) in 14 of these. Of the six
studies with a positive association between circumcision and risk of HIV, four
were from Mwanza [21-23], and none found a statistically significant
association. Overall, circumcision was associated with a highly significant
reduction in HIV risk (pooled RR=0.52; CI 0.40-0.68; Figure 1a; Table 2). There
was significant between-study heterogeneity (p<0.001).

Some adjustment for confounders was reported for 15 studies. Most studies
adjusted for age and one or more factors from the following: socio-demographic
(marital status, area of residence, ethnic group), sexual behaviour (number of
sexual partners in lifetime, last year or last four months, contact with sex
workers), and factors associated with risk of transmission (condom use, presence
of ulcerative STDs). Details are given in the footnote to Table 1. The study by
Barongo [23] was stratified by area of residence for the crude analysis, but
residence was included as a confounder in the multivariate analysis, and hence
this study contributes only once to the meta-analysis of adjusted effects. In
addition, one study reported no significant association after adjustment for
confounders but no details were given [39] and this study was not included in
the adjusted meta-analysis.

All the 15 studies reporting adjusted relative risks found a protective
effect of circumcision on HIV risk (RRs ranging from 0.12 to 0.8), and in 10
studies the effect was statistically significant (Table 1; Figure 1b). In
general, the effect of adjustment was to strengthen the association between
circumcision and reduced risk of HIV, with the adjusted RR being smaller than or
equal to the crude RR in 10 of the 14 studies which reported both measures. For
two studies from Mwanza [21, 22], the adjusted RR showed a decreased risk of HIV
among circumcised men although the crude RR had shown a non-significant
increased risk of HIV associated with circumcision. The four studies where the
adjusted RR was closer to one than the crude RR were the studies from the Ivory
Coast [32, 36] and of STD clinic attenders in Nairobi [38, 40]. In each of these
studies, the difference between the crude and adjusted RRs was small (Table
1).

Analyses were then stratified by type of population. The crude analysis
showed little evidence of an association between circumcision and HIV in
population-based studies (crude RR=0.93, CI 0.71-1.21). Of these 12 studies, six
adjusted for confounders. The crude RR was reported in five of the six studies
and was similar to that for all population-based studies (RR=0.90, CI
0.59-1.36). The adjusted RR showed a significantly decreased risk of HIV among
circumcised men (adjusted RR=0.56, CI 0.44-0.70, based on six studies; Table 2,
Figure 2a). There was no significant heterogeneity between these studies
(p=0.21). When analyses were restricted to cross-sectional studies alone,
results were very similar (crude RR=0.91, CI 0.63-1.32; adjusted RR=0.55, CI
0.42-0.72; Table 2).

Among the 12 studies of men at higher risk of HIV (STD clinic attenders,
truck drivers, TB patients and hospital patients), the crude RR was 0.27 (CI
0.22-0.33). Seven of these studies included adjustment for confounders, which
had little effect on the effect estimate (adjusted RR=0.29, CI 0.20-0.41; Table
2, Figure 2b). All adjusted RRs were 0.5 or less, but there was significant
between-study heterogeneity (p=0.03). Results for cross-sectional studies alone
were similar (crude RR=0.24, CI 0.20-0.29; adjusted RR=0.24, CI 0.18-0.31;
p-value for heterogeneity=0.49; Table 2).

Sensitivity analysis

There was wide variation in study size, with the largest study [28]
consisting of 6821 men (25% of the total subjects included in the
meta-analysis), whereas the second largest study consisted of 2603 men [21]. To
examine the influence of the largest study on the meta-analysis, we re-analysed
the data excluding this study. The resulting relative risks were similar (crude
RR=0.52, CI 0.40-0.68; adjusted RR=0.42, CI 0.32-0.55), indicating that this
study did not influence the meta-analysis unduly.

Funnel graphs of the data are presented in Figure 3a and 3b. There is no
evidence that smaller studies (i.e. those with larger standard error) were more
likely to report a positive association, indicating no evidence of publication
bias (Begg’s rank correlation test: p-value=0.56 for the crude analysis; p=0.24
for the adjusted analysis).

The effect of using the odds ratio instead of the risk ratio was assessed by
re-analysing the cross-sectional studies using the risk ratio. For these 18
studies, the crude odds ratio was 0.51 (CI 0.37-0.69) and the crude risk ratio
was 0.59 (CI 0.47-0.73). In the high risk studies, where HIV prevalence was
higher, the crude odds ratio was 0.24 (CI 0.20-0.29), and the crude risk ratio
was 0.37 (CI 0.33-0.41).

Discussion

This systematic review and meta-analysis provide compelling
evidence that male circumcision is associated with a reduced risk of HIV
infection in sub-Saharan Africa. The strongest association is seen among men at
high risk of HIV, but circumcised men in the general population are also at
significantly reduced risk after adjusting for potential confounding factors.
This supports results from the previous meta-analysis [14], which included 33
studies from around the world, and found an overall crude odds ratio of 0.60 (CI
0.45-0.80), with a stronger effect in high risk groups (crude OR=0.33, CI
0.26-0.43) than in general population groups (crude OR=1.04, CI 0.77-1.41). This
was a re-analysis of previously collected data and had several major limitations
(no systematic literature review, lack of adjustment for confounding factors,
and lack of exploration of heterogeneity), which have been addressed in the
present analysis.

Overall, there was significant heterogeneity between studies, indicating that
the magnitude of the protective effect varies between populations. We would,
however, expectany protective effect of circumcision to be heterogeneous
across different populations due to differences in a number of factors,
including variations in sexual exposure to HIV, timing of circumcision, but
particularly differences in the prevalence of STDs. There is evidence that male
circumcision protects against some ulcerative STDs (particularly chancroid and
syphilis) [3], which in turn enhance HIV transmission, and this could explain
the greater protection afforded by circumcision in populations where genital
ulcer disease (GUD) is more prevalent. Indeed, several studies adjusted
specifically for prior or current GUD, and as GUD is likely to act on the causal
pathway, the effect of circumcision on HIV may be stronger than that estimated
by an adjusted RR.

When the analysis was stratified by type of population, heterogeneity was
reduced substantially and was not significant in the population-based studies.
There was still significant heterogeneity among the seven high risk populations,
and the lack of reliable and consistent data from these studies on other
potential effect-modifiers (such as penile hygiene) prevented further
exploration of this heterogeneity. However, the studies all found a strong
protective effect (RRs from 0.12 to 0.50), and while this is a wide range, it
suggests that a substantial protective effect was a consistent finding in all
high risk populations.

The main limitation of observational studies is that the effect of
circumcision on HIV infection may be confounded by factors which are associated
with HIV risk, and which may differ between circumcised and uncircumcised men.
It is therefore important to note that adjustment for confounding strengthened
the association in all the population-based studies, and generally made little
difference in the high risk studies. This is not surprising, as most studies
which have reported behavioural patterns [21, 27, 28, 30, 33, 34, 42, 49] have
found that circumcised men tend to report higher risk behaviours than
uncircumcised men in the same population. This would tend to result in higher
HIV prevalence among circumcised men if there were no protective effect of
circumcision. It remains a possibility, however, that there is residual
confounding due to behavioural or biological factors that are unknown or poorly
measured in some studies.

Religion and ethnicity are potentially important confounding
factors in these observational studies, as they are likely to be associated with
both circumcision and HIV risk. Three studies explored this by stratifying
analyses by religion. Among Muslims in Kigali, Rwanda [42], circumcision was
associated with a protective effect (crude RR=0.18, CI 0.02-1.20). Little
association was seen among Christians (crude RR=0.79, CI 0.50-1.23) although
this could be because, unlike Muslims, most Christians were circumcised
post-puberty. A study in Rakai, Uganda [28], where 98.5% of Muslim men were
circumcised, found that among non-Muslim men, those circumcised before age 12
had a lower risk of HIV compared with uncircumcised men (crude RR=0.62, CI
0.29-1.28). Further, in Mwanza, Tanzania [22], the association between
circumcision and HIV was similar when results were re-analysed excluding
Muslims. Hence the evidence suggests that circumcision has an effect on HIV
infection independently of the confounding effect of religion.

It has been suggested that prepubertal circumcision (performed for religious
or traditional reasons) is more likely to protect against STDs and HIV, whereas
postpubertal circumcision is likely to be performed as a consequence of
infections, such as balanitis [28]. Only two studies included in the
meta-analysis asked about age at circumcision [22, 28]. In Rakai [28], the
strongest effect of circumcision on HIV risk was seen among those circumcised
below age 12 (adjusted RR=0.39, CI 0.29-0.53). There was also a significantly
reduced risk of HIV associated with circumcision between ages 13-20 (adjusted
RR=0.46, CI 0.28-0.77), and a non-significant effect above age 20 (adjusted
RR=0.78, CI 0.43-1.43). In contrast, among men in rural Mwanza [22],
circumcision before age 15 years was associated with an increased risk of HIV
(adjusted RR=1.50, CI 0.57-3.90), while circumcision after age 15 was associated
with a lower HIV risk (adjusted RR=0.37, CI 0.18-0.74). The reasons for these
discrepant findings are unclear, and further work on the effect of age at
circumcision on HIV susceptibility is needed.

The observational studies included in this meta-analysis cannot definitively
establish a causal role for circumcision in protecting against HIV infection. It
is biologically plausible that the foreskin may enhance HIV transmission both
directly and indirectly [50] although there is little direct evidence for this.
Causality also implies that circumcision occurs prior to infection with HIV, and
we cannot be certain of this with retrospective data, although the studies which
report age at circumcision [21, 22, 28, 42] indicate that it usually occurs by
age 20 and hence is likely to precede HIV infection.

The present analysis was restricted to studies of HIV infection in men. Hence
we were able to assess only the effect of circumcision on male susceptibility,
and not on male infectiousness. However, the advantages of this restriction are
considerable. Firstly, an effect of male circumcision on susceptibility is
arguably more plausible on biological grounds than an effect on infectiousness.
Secondly, only the circumcision status of the study subject is needed, and not
the status of partners, thus reducing potential misclassification of exposure.
Thirdly, a study of the effect of male circumcision on male-female transmission
is complex, as a woman may have had more than one male sexual partner, with
differing circumcision status. However, recent data from Rakai have shown that
among discordant couples in which the male partner was HIV positive, there was a
non-significant reduction in transmission rate if the man was circumcised (rate
ratio=0.44, CI 0.15-1.32), and this reduction in risk was statistically
significant among couples with male HIV viral loads < 50,000 copies per mL
[51].

Circumcision was determined by self-report in 16 studies, and by clinical
examination in eight studies. For four further studies [35-38] the method of
ascertainment was not clear. Validity of self-reported circumcision was assessed
among factory workers in Mwanza [21]. Of the 111 men who had reported they were
circumcised, only 69% were found to be so on examination. Among the 91 men who
reported themselves as uncircumcised, 94% were found to be uncircumcised on
examination. This suggests that self-reported circumcision may over-estimate the
proportion of men circumcised in this population, and suggests that genital
examination should be carried out whenever possible in future studies. Assuming
this misclassification is non-differential with respect to HIV status, the
effect would be to under-estimate the association between lack of circumcision
and HIV. All but one study performed HIV tests by one or two ELISA tests, with
confirmatory Western blot for discrepant or indeterminate ELISA results. The
remaining study [37] performed only one ELISA with no confirmatory testing.
Overall, therefore, there is likely to be little misclassification of HIV
results.

Meta-analyses are vulnerable to bias, due to failure to identify all eligible
articles and also because research yielding statistically significant results is
more likely to be submitted and published. Therefore, even if all published
studies have been identified, these may be only a subset of the studies actually
carried out. However, this seems unlikely to cause substantial bias in the
present review because studies of risk factors for HIV almost always examine a
range of behavioural and biological risk factors, and it is unlikely that the
published studies are biased in terms of finding circumcision as a risk factor.
However, it is possible that if no association with circumcision was found, this
was sometimes not mentioned in the paper. The results of the funnel plot suggest
that publication bias was not a problem in this meta-analysis, although the
existence of such bias cannot be excluded. It was decided to exclude conference
abstracts from the review as it is probable that these are more likely to report
significant than non-significant findings, and hence the inclusion of abstracts
might increase bias.

The 28 studies reviewed were from just eight countries, including nine
studies from Kenya (seven of these from Nairobi) and seven from Mwanza Region,
Tanzania. As expected, there were few studies from West Africa where
circumcision in most areas is almost universal, although 39% of men in the study
in Ziguinchor region, SW Senegal were uncircumcised [29].

To our knowledge, there have been two further studies on the effect of
circumcision on HIV infection published since our literature review. A cohort
study of trucking company employees in Kenya [52] found a very similar effect to
our summary measure for high risk populations (adjusted RR = 0.25, CI 0.1-0.5).
A recently published study of HIV discordant couples from Rakai, Uganda [53]
found that the rate of female-male transmission was significantly higher among
couples with uncircumcised male partners compared with couples with a
circumcised male partner (rates of 16.7 per 100 person-years compared with 0 per
100 person-years; p<0.001).

In conclusion, the data from observational studies provide compelling
evidence of a substantial protective effect of male circumcision against HIV
infection in sub-Saharan Africa, especially in populations at high risk of
HIV/STDs. The continuing rapid spread of HIV infection, especially in eastern
and southern Africa, suggests that the potential public health benefit of
introducing safe services for male circumcision on a wider scale should be
explored. However, there are many concerns around such an introduction,
including the possibility that men may increase their risky sexual behaviour if
they think circumcision confers a high degree of protection, as well as the risk
of bleeding or infection, cost, and issues of cultural identity. Studies are
therefore needed to examine the acceptability, feasibility and safety of
introducing male circumcision as an HIV/STD prevention strategy in high
prevalence areas where men do not traditionally circumcise. Results from one
such study among the Luo people in Nyanza province, western Kenya, who are
traditionally non-circumcising, showed that 60% of men would prefer to be
circumcised, and 62% of women would prefer a circumcised partner [54]. In areas
where male circumcision is acceptable to the local community, randomised
controlled trials of male circumcision performed by trained health workers as
part of a package intervention incorporating safe sex education are needed. Such
trials would overcome the inherent limitations of observational studies, and
allow for reliable empirical evidence on the overall impact of introduction of
male circumcision on HIV incidence.

Acknowledgements

We thank UNAIDS for funding this study, Michel CaraNl and Stephen Sharp for advice, and Simin
Bahrainipur for administrative assistance. Helen Weiss and Maria Quigley are
funded by the UK Medical Research Council.

References:

1. Buve A for the Study Group on Heterogeneity of HIV Epidemics in African
Cities: HIV/AIDS in Africa: Why So Severe, Why So Heterogeneous? 7th
Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, USA,
February 2000 [Abstract S28].

16 Adjusted for age, religion, education, residence, lifetime number of
sexual partners, lifetime number of contacts with sex workers, history of GUD or
non-ulcerative STD

17 Adjusted for age, religion, education, place of birth, number of partner
in last year, STD in last 4 months.

Table 2: Meta-analysis of the association between circumcision and risk of
HIV-1 infection among males in sub-Saharan Africa

Study population

Crude analysis

Adjusted analysis

N

RR (95% CI)

P for heterogeneity

N

RR (95% CI)

P for heterogeneity

All study designs:

All1

27

0.52 (0.40-0.68)

<0.001

15

0.42 (0.34-0.54)

<0.001

Population-based

12

0.93 (0.71-1.21)

0.008

6

0.56 (0.44-0.70)

0.21

High-risk

12

0.27 (0.22-0.33)

0.09

7

0.29 (0.20-0.41)

0.03

Cross-sectional studies only:

All

18

0.51 (0.37-0.69)

<0.001

11

0.42 (0.32-0.55)

<0.001

Population-based

7

0.91 (0.63-1.32)

0.003

5

0.55 (0.42-0.72)

0.17

High-risk

8

0.24 (0.20-0.29)

0.48

4

0.24 (0.18-0.31)

0.49

1 Includes crude relative risks for three studies [21, 42, 43] which
were not included in the sub-group analyses. Two of these [21, 42] also reported
adjusted relative risks.

Figure 1: Relative risk of HIV-1 infection associated with male
circumcision in 27 studies of males in sub-Saharan Africa. The black square and
horizontal line correspond to the relative risk and 95% confidence interval for
each study. The area of the black square reflects the weight of each trial. The
diamonds represent the combined relative risk and 95% confidence interval using
the random effects model.